P310: BH3 PROFILING IDENTIFIES SELECTIVE BCL-2 DEPENDENCE OF ADULT EARLY T-CCELL PROGENITOR AND TYPICAL ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS
Authors: K. Bhatia, A. Mahesh, E. Olesinski, J. Garcia, N. Jain, W. Y. Jen, M. Ooi Gaik Ming, A. Letai, M. Konopleva, S. Bhatt
Journal: HemaSphere (2022)

Background: T-cell acute lymphoblastic leukemia (ALL) results from malignant transformation of immature T-cells, accounting for 10-15% of childhood and 20-25% of adult ALL cases. Although long-term survival rates for standard-risk childhood T-cell ALL (T-ALL) have shown striking improvements to 90%, response outcomes in adults remain much lower. Among T-ALL, a high-risk subtype originating from clonal expansion of recently immigrated thymocytes, defined as early T-cell precursor (ETP) leukemias, has a significantly worse outcome in adults. Aims: BH3 mimetics, small molecule antagonists of anti-apoptotic BCL-2 family proteins, have shown remarkable clinical success in the treatment of hematological malignancies. We previously showed that pediatric ETP-ALL, is dependent on BCL-2, while typical T-ALL is dependent on BCL-XL. These findings importantly led to the clinical trial of venetoclax in combination with hyperCVAD in relapsed/refractory (R/R) T-ALL patients. However, whether adult patients with T-ALL also show the selective pattern of anti-apoptotic dependence related to the differentiation stage of T-cell has not been studied. Methods: BH3 profiling, and cell cytotoxicity assay. Results: We investigated the survival dependencies of adult ETP-ALL and T-ALL on BCL-2 family proteins using 42 primary samples collected from 3 centers (Dana-Farber, MD Anderson, and National Cancer Institute Singapore). All 15 ETP-ALL samples showed robust mitochondrial depolarization response to the BAD peptide as compared to the HRK peptide and DMSO control using BH3 profiling assay, suggesting primary dependence on pro-survival BCL-2 protein. We next performed cell death assays by exposing ETP-ALL primary tumors to short-term treatment with venetoclax and navitoclax and found that consistent with BCL-2 dependence, adult ETP-ALL can be efficiently targeted for apoptosis via venetoclax. We then asked if there is a difference in dependencies between adult ETP-ALL and T-ALL. In ETP-ALL, cytochrome c release was caused by the BAD peptide alone, while in T-ALL, both BAD and HRK peptides induced cytochrome c release. This suggests that ETP-ALL primary tumors are primarily BCL-2 dependent, while T-ALL primary tumors are co-dependent on BCL-2 and BCL-XL. Further, this dependence endorses mechanistic efficacy of venetoclax and navitoclax, where venetoclax serves to antagonize BCL-2, and navitoclax serves to antagonize BCL-XL and to a lesser extent BCL-2, through BIM displacement. Image:Summary/Conclusion: We hereby validated that BH3 profiling predicted remarkable on-target cytotoxicity of venetoclax in adult ETP-ALL and T-ALL. In addition, some T-ALL with enriched HRK signaling and BCL-XL dependence revealed that these patients can benefit from navitoclax. These findings provide pre-clinical evidence for venetoclax and navitoclax as a potentially efficacious combination therapy of BH3 mimetics for adults with T-ALL.